Journal of Zhejiang University SCIENCE B 1998 Vol.-1 No.-1 P.

http://doi.org/10.1631/jzus.B2600214


Drug repurposing: phenytoin sodium activates TBK1-dependent mitophagy to alleviate amyloid pathology and cognitive deficits in APP/PS1 mice


Author(s):  Ziyan CHEN1,2, Xufeng CEN2, Fengqi WANG2,3, Jinyu ZHANG1,2, Yanan TIAN2, Manke ZHANG2, Jie WU4, Xiaoyan XU2, Hongguang XIA2

Affiliation(s):  1. 1Department of Clinical Medicine, Zhejiang University School of Medicine, Hangzhou 310003, China more

Corresponding email(s):   jie_wu@fudan.edu.cn0016751@zju.edu.cnhongguangxia@zju.edu.cn

Key Words:  Alzheimer’s disease, Phenytoin sodium, Mitophagy, TBK1, Drug repurposing


Ziyan CHEN1, 2, Xufeng CEN2, Fengqi WANG2, 3, Jinyu ZHANG1, 2, Yanan TIAN2, Manke ZHANG2, Jie WU4, Xiaoyan XU2, Hongguang XIA2. Drug repurposing: phenytoin sodium activates TBK1-dependent mitophagy to alleviate amyloid pathology and cognitive deficits in APP/PS1 mice[J]. Journal of Zhejiang University Science B, 1998, -1(-1): .

@article{title="Drug repurposing: phenytoin sodium activates TBK1-dependent mitophagy to alleviate amyloid pathology and cognitive deficits in APP/PS1 mice",
author="Ziyan CHEN1, 2, Xufeng CEN2, Fengqi WANG2, 3, Jinyu ZHANG1, 2, Yanan TIAN2, Manke ZHANG2, Jie WU4, Xiaoyan XU2, Hongguang XIA2",
journal="Journal of Zhejiang University Science B",
volume="-1",
number="-1",
pages="",
year="1998",
publisher="Zhejiang University Press & Springer",
doi="10.1631/jzus.B2600214"
}

%0 Journal Article
%T Drug repurposing: phenytoin sodium activates TBK1-dependent mitophagy to alleviate amyloid pathology and cognitive deficits in APP/PS1 mice
%A Ziyan CHEN1
%A 2
%A Xufeng CEN2
%A Fengqi WANG2
%A 3
%A Jinyu ZHANG1
%A 2
%A Yanan TIAN2
%A Manke ZHANG2
%A Jie WU4
%A Xiaoyan XU2
%A Hongguang XIA2
%J Journal of Zhejiang University SCIENCE B
%V -1
%N -1
%P
%@ 1673-1581
%D 1998
%I Zhejiang University Press & Springer
%DOI 10.1631/jzus.B2600214

TY - JOUR
T1 - Drug repurposing: phenytoin sodium activates TBK1-dependent mitophagy to alleviate amyloid pathology and cognitive deficits in APP/PS1 mice
A1 - Ziyan CHEN1
A1 - 2
A1 - Xufeng CEN2
A1 - Fengqi WANG2
A1 - 3
A1 - Jinyu ZHANG1
A1 - 2
A1 - Yanan TIAN2
A1 - Manke ZHANG2
A1 - Jie WU4
A1 - Xiaoyan XU2
A1 - Hongguang XIA2
J0 - Journal of Zhejiang University Science B
VL - -1
IS - -1
SP -
EP - 0
%@ 1673-1581
Y1 - 1998
PB - Zhejiang University Press & Springer
ER -
DOI - 10.1631/jzus.B2600214


Abstract: 
Alzheimer’s disease (AD) is clinically characterized by progressive cognitive decline and pathologically by Aβ accumulation and tau aggregation. Current disease-modifying therapies remain limited, highlighting the need for brain-accessible agents that improve mitochondrial quality control. We screened more than 1000 FDA-approved drugs using an mt-Keima mitophagy reporter system and identified phenytoin sodium (PHT), a classical antiepileptic drug, as a candidate mitophagy inducer. In both cellular mitochon-drial stress models and APP/PS1 mice, PHT ameliorated mitochondrial ultrastructural damage, partially stabilized mitochondrial membrane potential, improved mitochondrial respiratory activity and cell viability, reduced Aβ burden and neuronal apoptosis, and significantly improved cognition. Mechanistically, PHT enhanced TBK1 phosphorylation at Ser172 and promoted mitophagic flux; genetic knockdown of TBK1, pharmacological inhibition of TBK1 with amlexanox, or mitophagy inhibition with Mdivi-1 attenu-ated PHT’s protective effects. Additional investigations in HeLa cells further suggested that PHT-associated mitochondrial clear-ance is not strictly dependent on Parkin and may involve TBK1-centered Parkin-independent mechanisms. These findings identify PHT as a clinically approved, brain-accessible compound that may alleviate AD-related pathology by enhancing TBK1-dependent mitochondrial quality control.

Darkslateblue:Affiliate; Royal Blue:Author; Turquoise:Article

Open peer comments: Debate/Discuss/Question/Opinion

<1>

Please provide your name, email address and a comment





Full Text:   <48>

CLC number: 

On-line Access: 2026-09-15

Received: 2026-04-04

Revision Accepted: 2026-05-30

Crosschecked: 0000-00-00

Cited: 0

Clicked: 52

Citations:  Bibtex RefMan EndNote GB/T7714

Journal of Zhejiang University-SCIENCE, 38 Zheda Road, Hangzhou 310027, China
Tel: +86-571-87952783; E-mail: cjzhang@zju.edu.cn
Copyright © 2000 - 2026 Journal of Zhejiang University-SCIENCE